Sj"gren's syndrome (SS) is a chronic autoimmune disorder characterized by salivary and lacrimal gland dysfunction, which manifests as the characteristic dry mouth and dry eye symptoms. Production of inflammatory cytokines within the glands is an important pathogenic factor. This proposal will investigate the role of innate immunity activation in the development of SS, with special emphasis on type I interferons (IFN). This proposal will test the hypothesis that localized production of type I IFNs within the salivary glands play a critical role in the pathogenesis of SS. Following specific aims are proposed: Aim 1. To demonstrate that activation of innate immune responses within the salivary glands is critical for inducing gland dysfunction. Aim 2. To demonstrate that type I IFN dictates lymphocytic infiltration into the SG and thereby influences localized adaptive immune responses within the SG. The experiments will be carried out in autoimmune prone NZB/W F1 mice. The role of type I IFNs will be directly addressed in mice lacking the interferon (alpha and beta) receptor 1 (IFNAR-/-). Innate immune responses will be activated using Toll-like receptor 3 agonist poly(I:C). To determine the effects of localized inflammation, poly(I:C) will be delivered into the salivary glands using retrograde instillation technique. In some experiments adenoviral vectors will be used to induce localized inflammation. The effects of type I IFN on SG chemokine production will be investigated and early cellular infiltrates characterized for corresponding chemokine-receptor expression. This proposal will demonstrate that type I IFNs exert their pathogenic effects by directly affecting the salivary gland function and by influencing the chemokine production by salivary gland epithelial cells. This will influence the inflammatory cell infiltration and thereby the adaptive immune responses within the salivary glands. The findings from this proposal will clarify the role of type I IFNs in the pathogenesis of SS and provide logical basis to therapeutically target the type I IFN pathway in SS. PUBLIC HEALTH RELEVANCE: The current proposal will identify the mechanisms for dry mouth syndrome, a common complication of Sj"gren's syndrome. The proposed studies will develop novel mouse models to study pathological mechanisms responsible for salivary gland damage and loss of function.